Cancer is a major public health problem in the United States and many other parts of the world. It is currently the second leading cause of death in the United States, and is expected to surpass heart diseases as the leading cause of death in the next few years. It remains a major cause of mortality in the world. Despite the improvements that have been made in therapies and in understanding the molecular basis of cancer, mortality is still high. The current treatment regimens for cancer have shown limited survival benefits when used for most advanced stage cancers.
The research and efforts being invested for cancer treatment has changed over the past few decades. The age when surgery and radiotherapy were the only effective ways to fight tumor growth has ended. A complex scenario where the molecular features of tumors seem to be the cornerstone of any therapy is now emerging with new targets or receptors being discovered in vivo. Continued research has expanded knowledge of how cancer develops and how to target medicines for specific cancer types, which has resulted in more effective therapies for patients. However these therapies show a lack of efficacy in terms of long-term outcome because of their failure to target cancer cells and lead to toxicity due to non-specific effects on normal cells. To overcome these side effects, researchers have tried to understand the root cause and have explored more about the gene changes in cells that cause cancer, they have been able to develop drugs that target these changes. Targeted therapy drugs does not work in the same way as the standard chemotherapy drugs. They are often able to attack cancer cells while doing less damage to normal cells by targeting the programming of cancer cells that sets them apart from normal, healthy cells. These drugs tend to have different (and often less severe) side effects than standard chemotherapy drugs. Examples of the targeted therapies include sorafenib, sunitinib, bevacizumab, telomerase etc.
Research on apoptosis has increased substantially since the early 1990s. Apoptosis (programmed cell death)-inducing drugs change proteins within the cancer cells and cause the cells to die.
Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. The two pathways both activate initiator caspases, which then activate executioner caspases, which then cause cell apoptosis by degrading proteins indiscriminately.
Induction of apoptosis in malignant cells therefore becomes a major goal of cancer therapy in general and of certain cancer gene therapy strategies in particular. Numerous apoptosis-regulating genes have been evaluated for this purpose for example p53 gene, p16, p21, p27, E2F genes, FHIT, PTEN, E1A and CASPASE genes.
The prostate apoptosis response-4 (PAR-4) gene was first identified by the differential hybridization technique as an immediate early apoptotic gene upregulated in response to elevated intracellular Ca2+ concentration [Ca2+] in the androgen-independent rat prostate cancer cells AT-3 treated with ionomycin.
Studies conducted in cell culture models show that over-expression of PAR-4 is sufficient to directly induce apoptosis in many cancer cell types. The ability of PAR-4 to directly cause apoptosis is associated with its nuclear translocation. Moreover, the apoptotic action of PAR-4 can overcome cell protective mechanisms, such as the presence of Bcl-xL, Bcl-2, or absence of wild-type p53 or PTEN function. Interestingly, PAR-4 is incapable of directly inducing apoptosis in normal or immortalized normal cells.
The “apoptosis-sensitizing” function of PAR-4 in some of the cancer cells is attributed to its accumulation in the cytoplasm and inability to translocate into the nucleus, due to phosphorylation by Aktl which renders PAR-4 subject to sequestration in the cytoplasm by complexing it with chaperone proteins such as 14-3-3; however, treatment with the other apoptotic signals translocates PAR-4 into the nucleus to produce apoptosis. Renal cell carcinoma (RCC, also known as hypernephroma) is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that transport GF (glomerular filtrate) from the glomerulus to the descending limb of the nephron. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases. It is also known to be the most lethal of all the genitourinary tumors. Initial treatment is most commonly a radical or partial nephrectomy and remains the mainstay of curative treatment. Where the tumor is confined to the renal parenchyma, the five year survival rate is 60-70%, but this is lowered considerably once metastases have spread. It is relatively resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy.
Renal-cell carcinoma affects approximately 150,000 people worldwide each year, causing close to 78,000 deaths annually, and its incidence seems to be increasing. RCC is not a single entity, but rather comprises the class of tumors of renal epithelial origin. Extensive histological and molecular evaluation has resulted in the development of a consensus classification of different RCC subtypes: (i) conventional (clear-cell) renal cell carcinoma; (ii) papillary renal cell-carcinoma; (iii) chromophobe renal carcinoma; (iv) onco-cytoma; (v) collecting-duct carcinoma. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal cancer accounts for 1-4% of cases and could involve the same genes that cause sporadic renal cancer. Over the past two decades, studies of families with inherited RCC have laid the groundwork for the identification of seven hereditary renal cancer syndromes, and the predisposing genes for five of these have been identified. The surprisingly diverse nature of these genes implicates various mechanisms and biological pathways in RCC tumorigenesis.
RCC can be treated using surgery, radiation therapy, immunotherapy, and molecular-targeted therapy. Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it is also used for palliation in metastatic disease. Targeted therapy and immunomodulatory agents are considered standard of care in patients with metastatic disease.
Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates with chemotherapy, either single-agent or combination, are usually lower than 15%. Therefore, various therapies have been evaluated.
The first agent, approved in late 2005, was sorafenib, after showing improvement in the second-line setting for progression-free survival (PFS) versus placebo. Shortly thereafter, sunitinib was approved following a large phase III trial that also demonstrated improvement in PFS versus interferon-α (INFα) in the first-line setting. The next agent approved was the mechanistic target of rapamycin (serine/threonine kinase) (mTOR) inhibitor, temsirolimus, which was evaluated as a first-line therapy against INFα in patients, most of whom had poor-risk disease. This trial demonstrated an improvement in overall survival (OS) in patients receiving temsirolimus. Combination of temsirolimus and INFα showed no advantages over the mTOR inhibitor alone. Meanwhile, everolimus was the second mTOR inhibitor approved after second-line therapy showed improvement in PFS versus placebo in a clinical trial. Pazopanib and axitinib are the two newer tyrosine kinase inhibitors and were recently approved for treatment of metastatic RCC. Patients taking pazopanib exhibited improved PFS versus those taking placebo both in the first-line setting and for cytokine-refractory disease. Axitinib was studied against sorafenib as a second-line agent and demonstrated improved PFS, while patient preference studies with pazopanib suggested improved tolerability. Yet another class of drug, an anti-PD-1 checkpoint inhibitor named nivolumab, has been approved for intravenous administration that unleashes the body's immune system to fight the cancer cancer, however, the drug may cause the body to develop an immune reaction against its own tissues thereby leading to wide range of side effects that can be severe or life-threatening. With multiple approved agents available, further research is yet to define the ideal timing, sequencing, and patient profile for a given particular agent.
Although, studies have demonstrated the general tolerability of targeted agents, in most instances, patients with RCC typically develop resistance to targeted agents after a median of 5-11 months of treatment. Combinations of targeted agents are being evaluated, but toxicity is problematic. Several strategies have been tested to manage the drug resistance including: Adjusting the dose of the drug, combination therapy or switching to an alternative agent. Moreover alternative pathways are currently under investigation particularly targeting of RAF (Rapidly Accelerated Fibrosarcoma), MEK (Mitogen-activated protein/extracellular signal-regulated kinase), and the PI3K (Phosphatidylinositol 3-kinase)/AKT (a serine/threonine kinase also known as protein kinase B [PKB]) pathway.
Based on the information available, even though there have been some advancements in the treatment of renal cell carcinomas, the associated complications like the disease stage, the response rate and the accompanying side effects potentially reduce the patient compliance and poses issues which severely affect the progression-free survival (PFS) and/or the overall survival (OS) which is the ultimate treatment goal for a given therapy.
Thus there is a need for improved methods for treating cancer. There remains a need for selective PAR-4 agonists. There remains a need for identifying selective PAR-4 agonists useful in the treatment of cancer. There remains a need for improved and additional methods of treating renal cell carcinoma. There remains a need for additional small-molecule therapeutics for the treatment of renal cancer.